This proposal seeks to correlate biochemistry with changes in motor function after selective lesions of individual raphe nuclei. During our first three years, we unexpectedly found that unilateral lesions of 5-HT pathways produced a turning syndrome typical or dopaminergic hyperfunction and associated with increased DA synthesis on the side of the lesion. Our chemical lesions of 5-HT pathways cause turning resembling that described by Ungerstedt, except that apomorphine and amphetamine cause turning in the same direction. After unilateral nigrostriatal lesions, these drugs cause turning in opposite directions. Also unexpected was the fact that our rats always recover after a few weeks and that chemical abnormalities recover in parallel with the motor behavior. We believe that turning in our rats results from disinhibition of the nigrostriatal DA neurons by removal of inhibitory input to the substantia nigra. Turning provides external evidence of events at striatal DA receptors, and its disappearance signals that chemical compensation has occurred. Abnormalities of transmitter turnover are predictable from the presence or absence of turning. We now propose to develop a multi-dimensional analysis of this model motor behavior which is relevant to human diseases of the extrapyramidal motor system. Anatomical studies are needed to correlate biochemistry and our behavior, because the relevant pathways are incompletely known and the wiring diagram is an essential step in understanding how the nigrostriatal system interacts with the rest of the brain. Our model will be used to help analyze the turning shown by a new mutant mouse, the belted circler, which appears to have an asymmetrical nigrostriatal system. The recovery shown by our rats can help us learn more about mechanisms of recovery from brain injuries. We shall also study the effect of treatment with 5-HT precursors and choline upon the rate of recovery.